Purine compounds are found in mammalian organisms both intracellularly and extracellularly, and play vital roles in metabolic processes. A nonlimiting example of the ubiquitous nature of purine compounds in mammalian systems is the purine containing nucleoside adenosine, which was reported over 60 years ago to relax coronary vascular smooth muscle and to impair atrioventricular conduction; adenosine has also been found to have antinociceptive properties and has recently been proven to be useful as an anesthetic. The widespread actions of adenosine include effects on the cardiovascular, nervous, respiratory, gastrointestinal, renal and reproductive systems, as well as on blood cells, adipocytes, and immune systems. Very small doses of adenosine (0.01-0.25 mg/kg), provided as a single bolus injection, have been suggested for the treatment of supraventricular tachycardia. A continuous intravenous infusion of up to 0.2 mg/kg/min adenosine for a duration of about 6 minutes has been also suggested for use in diagnostic myocardial imaging. Likewise, the phosphorylated adenosine nucleoside, or adenosine nucleotide, has also been found useful in inducing an anesthetic effect (a phosphorylated nucleoside is a nucleotide). Use of adenosine compounds in anesthesia is discussed in more detail in U.S. Pat. No. 5,677,290, entitled THERAPEUTIC USE OF ADENOSINE COMPOUNDS. The method described in U.S. Pat. No. 5,677,290 involves a great improvement in anesthesia by administering up to 5 mg/kg/min adenosine or ATP to a mammal via a continuous infusion; the dosage is adjusted in response to cardiovascular changes which are due to surgical stimulation. At the dosages used, the anesthetic effect is slowly induced, and the patient must be carefully monitored. It is believed that the slow induction of an anesthetic effect is due to the low dosage of adenosine provided, but it was not believed safe to increase the dosages to more quickly achieve an anesthetic effect.
It is believed that the activity of purine compounds is mediated by cell surface receptors specific for a particular purine compound. Depending on a compound and its receptor, binding of the compound to the receptor can be reversible, and have a variety of effects. Further, it is believed that certain compounds can bind to more than one receptor in a competitive fashion with other compounds. In a process, sometimes referred to as biofeedback, the binding of a first compound to a particular receptor or the presence of a first compound may induce the body to produce another agent which counteracts one or more of the effects of the first compound. For example, endogenous substances known as catecholamines, such as those produced by the nerve endings and the adrenal glands, may be released in response to a stressful situation (e.g., norepinephrine, epinephrine, and dopamine). For example, the endogenous production/release of tiny amounts of catecholamines causes increased heart rate and vasoconstriction, which the body responds to by the production of tiny amounts of adenosine and ATP which are believed to counteract certain of the effects of the increased endogenous catecholamines by different receptor mechanisms.
Considerable research has been directed to purine compounds since Drury and Szent-Gyorgyi reported in 1929 on the physiological actions of adenosine on cardiovascular function. Several classes of purine receptors have been identified, and adenosine and adenosine triphosphate, ATP, have been demonstrated as endogenous protective substances. Although certain purine compounds have significant beneficial physiological capabilities, the aforementioned ubiquitous nature and effects of purine compounds also tends to make it difficult to use them therapeutically. In other words, administration of purine compounds to a mammal will have both desired and undesired effects depending on patient physiology and the dosages provided.
Furthermore, because these purine compounds such as adenosine are considered toxic at concentrations that have to be administered to a patient to maintain efficacious extracellular therapeutic level, the administration of adenosine alone has been considered of no use or limited therapeutic use. Therefore, pharmacologists have directed their efforts to achieving high local extracellular level of adenosine by a) inhibiting the uptake of adenosine with reagents that specifically block adenosine transport; b) prevention of the metabolic degradation of adenosine; c) the use of adenosine analogs which will bind to specific adenosine receptors; and recently d) the use of adenosine via its precursor, AICA riboside, which has been the subject of a number of publications and patents (U.S. Pat. Nos. 5,082,829; 5,132,291; 5,187,162; 5,200,525; 5,236,908). However, the above approaches still have major disadvantages associated with their use. The metabolic and uptake blocker strategy is very much restricted in character due to the limited ability of tissue to generate purine compounds, and the adenosine agonist approach has the substantial peripheral side effects associated with these agents, such as hypotension, bradycardia, etc. Thus, despite all the intense efforts in basic sciences and pharmaceutical research, to this date, there has been little success in developing agents that can be used as therapeutic drugs to fully activate purine receptors without side effects. Therefore, until now, there has been no successful medical treatment for prevention or treatment of ischemic damage.
For more information on purine compounds and purine receptor agonists, see Ely et al., "Protective Effects of Adenosine in Myocardial Ischemia", Circulation, 85: 893-904 (1992); Miller et al., "Therapeutic Potential for Adenosine Receptor Activation in Ischemic Brain Injury," J. Neurotrauma, 9: 563-77 (1992); Williams, "Adenosine Receptors as Drug Targets: Fulfilling the Promise?," in Jacobson et al., Ed., Purine in Cellular Signaling: Targets for New Drugs, New York, Springer-Verlag (1990)(See particularly page 175); Lawson et al., "Preconditioning: State of the Art Myocardial Protection," Cardiovascular Research, 27: 542-50 (1993); Rudolphi, "Manipulation of Purinergic Tone as Mechanism for Controlling Ischemic Brain Damage," in Phillis, J. W., Ed., Adenosine and Adenine Nucleotides as Regulators of Cellular Function, Boca Raton, CRC Press (1991); Berne, R., "Adenosine--a Cardioprotective and Therapeutic Agent," Cardiovascular Research, 27:2 (1993); Phillis et al., "Roles of Adenosine and Adenine Nucleotides in the Central Nervous System," in Daly et al., Eds., Physiology and Pharmacology of Adenosine Derivatives, Raven Press, New York (1983); Galinanes, "Should Adenosine Continue To Be Ignored As A Cardioprotective Agent In Cardiac Operations?," Journal of Thoracic and Cardiovascular Surgery, 105: 180-183 (1993); Jacobson et al., "Novel Therapeutics Acting Via Purine Receptors," Biochemical Pharmacology 41: 1399-1410 (1991); U.K. Patent 797,237; U.S. Pat. No. 4,514,405; U.S. Pat. No. 4,590,180; U.S. Pat. No. 4,605,644; U.S. Pat. No. 4,673,563; U.S. Pat. No. 4,880,783; U.S. Pat. No. 4,880,918; U.S. Pat. No. 5,049,372; U.S. Pat. No. 5,070,877; U.S. Pat. No. 5,104,859; Daval et al., "Physiological and Pharmacological Properties of Adenosine Therapeutic Implications," Life Sciences 49: 1435-1453 (1991); Dubyak et al., Eds., Biological Actions of Extracellular ATP, Annals of the New York Academy of Sciences v. 603, New York, N.Y. Academy of Sciences (1990); Imai et al., Eds., Role of Adenosine and Adenine Nucleotides in the Biological System. Metabolism, Release, Transport. Receptors, Transduction Mechanisms and Biological Actions, Amsterdam, Elsevier (1991); Ribeiro, Ed., Adenosine Receptors in the Nervous System, London, Taylor & Francis (1989); Williams, Ed., Adenosine and Adenosine Receptors, Clifton, N.J. The Humana Press (1990); Tsuchida et al., "Pretreatment with the adenosine A.sub.1 selective agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), causes a sustained limitation of infarct size in rabbits," Cardiovascular Research, 27:652-66 (1993); Fukunaga et al., "Hypotensive effects of adenosine and adenosine triphosphate compared with sodium nitroprusside," Anesthesia and Analgesia 61:273-278 (1982); Fukunaga et al., "Effects of intravenously administered adenosine and ATP on halothane MAC and its reversal by aminophylline in rabbits," Anesthesiology, 71:A260 (1989); Drury et al. "The physiological activity of adenine compounds with special reference to their action upon the mammalian heart", Journal of Physiology (London) 68:213-37 (1929); Olsson et al. "Cardiovascular purinoceptors," Physiological Reviews, 70:761-809 (1990); Downey et al., Ed. "Spotlight on the cardioprotective properties of adenosine", Cardiovascular Research, v. 27, No. 1 whole issue (1993); Rudolphi et al., Neuroprotective role of adenosine in cerebral ischemia," Trends in Pharmacological Sciences, 13:439-45 (1992); and Williams, "Purinergic pharmaceuticals for the 1990s," Nucleosides & Nucleotides, 10:1087-99 (1991); U.S. Pat. Nos. 5,082,829; 5,132,291; 5,187,162; 5,200,525; 5,236,908; Homeister et al., "Combined adenosine and lidocaine administration limits myocardial reperfusion injury," Circulation 82:595-608 (1990); Mullane K, "Acadesine: the prototype adenosine regulating agent for reducing myocardial ischaemic injury," Cardiovascular research 27:43-7 (1993); Van Belle H, "nucleoside transport inhibition: a therapeutic approach to cardioprotection via adenosine?," Cardiovascular Research 27:68-76 (1993); all of which are incorporated by reference. Perhaps the greatest problem with attempts to utilize purine compounds as therapeutic agents is due to the undesired and often fatal side effects associated with providing sufficient amounts of a purine compound to a patient to induce a desired effect. For example, it has been well documented that adenosine plays a key role in the endogenous defenses of the brain against the damaging effects of ischemia. Moreover, adenosine has been reported to protect the heart when given both prior to ischemia and at reperfusion; however, intravenous administration of adenosine or even an A.sub.1 selective agonist has been shown to cause profound hypotension (A.sub.1 represents one of the purported adenosine receptors in mammalian systems). In another example, anesthesia is induced in a mammal by administering large amounts of adenosine or ATP; however, anesthetically effective dosages can be fatal to the recipient if extreme care is not followed in administering same (e.g., titration of adenosine in response to accurate monitoring of patient vital signs) or if a counteracting agent is not provided promptly in response to dangerous patient vital function levels. Even with prior or subsequent provision of agents to counteract certain undesired effects of administering the large dosages of adenosine, or an adenosine analog, sufficient to induce anesthesia, dangerous variations in vital functions can result. This "pendulum effect" on patient physiological processes, which is reflected in large changes in patient vital signs, such as but not limited to blood pressure, heart rate, and respiration, discourages the therapeutic use of purine compounds.
Therefore, there is a need for purine compositions comprising a purine compound which can be more easily and safely administered in a sufficient amount to induce a desired effect without inducing an undesired effect which is usually associated with administering the same amount of purine compound alone. Most prior attempts to counteract the undesired effects of administering a purine compound have involved the use of receptor specific antagonists. Furthermore, it was believed that, due to the dissimilar structure and function of the purine compounds with respect to the agents which counteract certain undesired effects of administering the purine compounds, that the purine compounds and counteracting agents could not be simultaneously used or mixed together in-vitro and still be safely administered for therapeutic purposes.